Application of water-soluble or water-dispersible polymerizates which contain poly-ether and which are used as a coating agent, a binding agent and/or as a film-forming auxiliary agent in pharmaceutical forms of administration

ABSTRACT

The use of polymers which are obtainable by polymerization of 
     a) at least one vinyl ester of aliphatic C 1 -C 24 -carboxylic acids in the presence of 
     b) polyethers of the general formula I,                    
      in which the variables have, independently of one another, the meanings mentioned in the description, as coating agent, binder and/or film-forming excipient in pharmaceutical presentations.

The invention relates to the use of water-soluble or water-dispersiblepolyether-containing polymers as coating agent, binder and/orfilm-forming excipient in pharmaceutical presentations.

Solid pharmaceutical presentations such as tablets, capsules, pellets,granules, crystals etc. are provided with a film coating for a widevariety of reasons. It is possible in this way, for example, to mask anunpleasant odor or taste, and improve the swallowability. The stabilityof the active ingredient can be increased by the coating, since lesswater vapor and oxygen reaches the interior of the tablets. Thepresentations have a better appearance and can be distinguished betterby incorporating dyes. In addition, in particular the rate of release ofthe active ingredient can be adjusted by the film coating.

A distinction is made in general between instant release forms and slowrelease forms.

In the case of instant release forms, the disintegration of the tabletand the release of the active ingredient from the presentation should,where possible, be unaffected by the coating, for which reason the filmcoating must dissolve rapidly in gastric fluid. In addition, it musthave good film properties. The tensile strength and the ultimateelongation should be high so that the film coating withstands mechanicaleffects like those occurring during pharmaceutical processing—especiallypackaging—and during transport and storage.

A product which is frequently employed for coating instant releasetablets is hydroxypropylmethylcellulose (HPMC).Hydroxypropylmethylcellulose shows a steep rise in viscosity withincreasing concentration in aqueous solution. Hydroxypropylcellulose(HPC) also shows a similar behavior.

Since the film former solution must be finely atomized for coatingtablets, and the drops which are formed must thoroughly wet the surfaceof the tablets, and moreover spread well, the viscosity must not exceeda certain limit (between 150 and 250 mPas) which depends on the type ofspray nozzle and the equipment. It is therefore possible in the case ofHPMC to employ only relatively low film former concentrations.

The recommendation given in the literature for the concentration ofPharmacoat® 606 (from Shin-etsu) is 5 to 7% by weight (PharmaceuticalCoating Technology, edited by Graham Cole, Taylor and Francis Ltd. 1995and manufacturers' technical data sheet). These low spray concentrationsresult in relatively long processing times and thus high costs.

In addition, hydroxypropylmethylcellulose has other disadvantages, interalia in the wetting characteristics, in the adhesiveness on the tabletsurface, in the pigment binding capacity, in the mechanical propertiesof the films, in the hygroscopicity and in the permeability for watervapor and oxygen, in the rate of dissolution and in the difference indisintegration time between film-coated tablets and core.

The low elasticity of hydroxypropylmethylcellulose films frequentlyleads to the film-coated tablets splitting open on storage in moistconditions, as a consequence of the swelling of the core. Even the useof plasticizers results in negligible improvements in this problem. Onthe contrary, it might lead to tacky films and, through migration, tochanges in the tablet properties.

Oral drug forms which release the medicinal substance over a lengthyperiod with the aim of prolonging the effect of the active component(generally slow release drug forms) are becoming increasingly important.They are associated with the advantages of improved patient compliancethrough a reduced frequency of intake, a reduction in side effectsthrough avoidance of plasma peaks, more uniform blood levels of themedicinal substance, and the avoidance of local irritation. Besides theformulation of medicinal substance-containing cores which are coatedwith a film which is insoluble in water but is semipermeable or containspores through which the medicinal substance diffuses, release can becontrolled and prolonged by embedding the medicinal substance inmatrices. It is possible in addition to use ion exchange resins andtherapeutic systems (e.g. OROS).

Embedding of the medicinal substance in hydrocolloid matrices inparticular provides the advantages of simple and low-cost manufactureand a high degree of drug safety because no dose dumping effects canoccur. The excipients normally employed for this purpose such ashydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose, alginicacid or alginates, and xanthan have disadvantages on use. Those whichmay be mentioned are: deficient flow properties which makes directtableting difficult, a dependence of the release of medicinal substanceon the osmolarity (salt content) and on the pH of the release medium.This applies equally to HPMC and to hydroxypropylcellulose, xanthan andalginates. The use of xanthan moreover results in tablets whose hardnessis low, and the direct tableting of alginates results in compacts withonly slight release-slowing properties (max. 8 h). The natural swellingsubstances (e.g. alginates) show overall a wide variability betweenbatches.

It has been found, surprisingly, that the polymers described hereinafterdo not have these disadvantages and are advantageous for use as matrixfor release of the active ingredient in oral pharmaceuticalpreparations.

Binders are employed in pharmaceutical presentations in order toincrease the processability and the mechanical strength. They arenormally employed in tablets, granules and pellets and result inimproved flowability, greater hardness and less friability.

The binders used at present such as maltodextrin orpolyvinylpyrrolidones frequently do not result in satisfactoryhardnesses and friabilities. Other binders such as starch paste andhydroxypropylmethylcellulose (HPMC) can be employed only in lowconcentrations because of their high viscosity.

In addition, film-forming excipients are employed in solutions andsprays which are applied to the skin or mucous membrane or elseintroduced systemically into the body. Examples thereof are preparationsfor wound treatment and spray-on dressings, but also preparations forapplication to intact skin or mucous membrane. In this case, the skin isprotected by a film, and the active ingredients can penetrate into orthrough the skin.

Great flexibility is necessary for transdermal therapeutic systems andfor wound plasters, just as for the abovementioned presentations, butthe products available at present do not have this. The use of possibleplasticizers to achieve the necessary flexibility is undesirable fortoxicological and pharmacological reasons.

It is an object of the present invention to provide water-soluble orwater-dispersible polymers as coating agents, binders and/orfilm-forming excipients in pharmaceutical presentations which do nothave the abovementioned disadvantages.

We have found that this object is achieved by the use of polymers, inparticular polymers which are soluble or dispersible in water and areobtainable by polymerization of

a) at least one vinyl ester of aliphatic C₁-C₂₄-carboxylic acids, in thepresence of

b) polyethers of the general formula I,

 in which the variables have, independently of one another, thefollowing meanings:

R¹ hydrogen, C₁-C₂₄-alkyl, R⁹—C(═O)—, R⁹—NH—C(═O)—, polyalcohol residue;

R⁸ hydrogen, C₁-C₂₄-alkyl, R⁹—C(═O)—, R⁹—NH—C(═O)—;

R² to R⁷

—(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —CH₂—CH(CH₃)—, —CH₂—CH(CH₂—CH₃)—,—CH₂—CHOR¹⁰—CH₂—;

R⁹ C₁-C₂₄-alkyl;

R¹⁰ hydrogen, C₁-C₂₄-alkyl, R⁹—C(═O)—;

A —C(═O)—O—, —C(═O)—B—C(═O)—O—, —C(═O)—NH—B—NH—C(═O)—O—;

B —(CH₂)_(t)—, arylene, optionally substituted;

n 1 to 8;

s 0 to 500;

t 1 to 12;

u 1 to 5000;

v 0 to 5000;

w 0 to 5000;

x 1 to 5000;

y 0 to 5000;

z 0 to 5000

as coating agent, binder and/or film-forming excipient in pharmaceuticalpresentations.

Graft polymers containing polyalkylene oxides have already beendisclosed inter alia as ancillary substances in pharmaceuticalpreparations.

Thus, DE-A-23 63 853 describes the use of partially hydrolyzed graftcopolymers of vinyl acetate onto polyethylene glycol for producingself-supporting packs or capsules for medicines. These capsules producedfrom the graft copolymers are intended to be employed as alternatives toknown hard gelatin capsules as described, for example, in Pharmazie inunserer Zeit, 23(4), 226-229 (1994). There is no mention in thispublication of the use of graft copolymers as coating agents or bindersfor pharmaceutical presentations.

DE 1 077 430, DE 1 094 457 and DE 1 081 229 describe processes forproducing graft copolymers of polyvinyl esters and their use aswater-soluble packaging films and as ancillary substances in cosmetics.

DE 43 36 493 describes water-soluble oxyalkylene group-containingpolyvinyl alcohol resin compositions and their use for example aspacking materials.

The polymers used according to the invention are graft copolymers inwhich in general polyethers of the general formula I selected from thegroup consisting of polyalkylene oxides based on ethylene oxide,propylene oxide and butylene oxide, and polyglycerol, are used asgrafting base b). Depending on the nature of the monomer buildingblocks, the resulting polymers have the following structural units.

—(CH₂)₂—O—, —(CH₂)₃—O—, —(CH₂)₄—O—, —CH₂—CH(CH₃)—O—,—CH₂—CH(CH₂—CH₃)—O—, —CH₂—CHOR⁷—CH₂—O—;

These may be both homopolymers and copolymers, and the copolymers mayhave a random distribution or be in the form of block copolymers.

Depending on the degree of grafting, the polymers used according to theinvention comprise both pure graft copolymers and mixtures of theabovementioned graft copolymers with ungrafted polyethers of the formulaI and homo- or copolymers of monomers a) and, where appropriate, othermonomers c).

The terminal primary hydroxyl groups in the polyethers produced on thebasis of alkylene oxides or glycerol and, in addition, the secondary OHgroups of polyglycerol can be both in free, unprotected form andetherified with alcohols with a chain length of C₁-C₂₄ or esterifiedwith carboxylic acids with a chain length of C₁-C₂₄.

Alkyl radicals which may be mentioned for R¹ and R⁸ to R¹⁰ are branchedor unbranched C₁-C₂₄-alkyl chains, preferably methyl, ethyl, n-propyl,1-methylethyl, n-butyl, 1-methylpropyl-, 2-methylpropyl,1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl,3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl,3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl,1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl,n-heptyl, 2-ethylhexyl, n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl,n-tridecyl, n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl,n-octadecyl, n-nonadecyl or n-eicosyl.

Preferred representatives which may be mentioned of the abovementionedalkyl radicals are branched or unbranched C₁-C₁₂-, particularlypreferably C₁-C₆-alkyl chains.

The number average molecular weight of the polyethers is in the rangebelow 500000, preferably in the range from 300 to 100000, particularlypreferably in the range from 500 to 20000, very particularly preferablyin the range from 800 to 15000.

It is advantageous to use homopolymers of ethylene oxide or copolymerswith an ethylene oxide content of from 40 to 99% by weight. Thus, thecontent of ethylene oxide units in the ethylene oxide polymers to bepreferably employed is from 40 to 100 mol %. Suitable as comonomers forthese copolymers are propylene oxide, butylene oxide and/or isobutyleneoxide. Suitable examples are copolymers of ethylene oxide and propyleneoxide, copolymers of ethylene oxide and butylene oxide, and copolymersof ethylene oxide, propylene oxide and at least one butylene oxide. Theethylene oxide content in the copolymers is preferably from 40 to 99 mol%, the propylene oxide content is from 1 to 60 mol % and the butyleneoxide content in the copolymers is from 1 to 30 mol %. Not onlystraight-chain but also branched homo- or copolymers can be used asgrafting base.

Branched polymers can be produced by, for example, addition of ethyleneoxide and, where appropriate, also propylene oxide and/or butyleneoxides or polyglycerol onto low molecular weight polyalcohol residues(=R¹ in the general formula I, such as, for example, pentaerythritol,glycerol or sugars or sugar alcohols such as sucrose, D-sorbitol andD-mannitol).

The polymers which may be formed in these cases are ones in which atleast one, preferably one to eight, particularly preferably one to five,of the hydroxyl groups present in the polyalcohols can be linked in theform of an ether linkage to the following polyether residue P as shownin formula I

The alkylene oxide units may be randomly distributed or present in theform of blocks in the polymer.

However, it is also possible to use polyesters of polyalkylene oxidesand aliphatic C₁-C₁₂-, preferably C₁-C₆-dicarboxylic acids or aromaticdicarboxylic acids, e.g. oxalic acid, succinic acid, adipic acid orterephthalic acid with molecular weights of from 1500 to 25000,described in EP-A-0 743 962, as grafting base.

It is also possible to use polycarbonates produced by phosgenation ofpolyalkylene oxides or polyurethanes from polyalkylene oxides andaliphatic C₁-C₁₂-, preferably C₁-C₆-diisocyanates or aromaticdiisocyanates, e.g. hexamethylene diisocyanate or phenylenediisocyanate, as grafting base. The abovementioned polyesters,polycarbonates or polyurethanes may contain up to 500, preferably up to100, polyalkylene oxide units, it being possible for the polyalkyleneoxide units to consist both of homopolymers and of copolymers ofdifferent alkylene oxides.

The polymers preferably used are obtainable by polymerization of

a) at least one vinyl ester of aliphatic C₁-C₂₄-carboxylic acids in thepresence of

b) polyethers of the general formula I,

in which the variables have, independently of one another, the followingmeanings:

R¹ hydrogen, C₁-C₂₄-alkyl, R⁹—C(═O)—, polyalcohol residue;

R⁸ hydrogen, C₁-C₂₄-alkyl, R⁹—C(═O)—;

R² to R⁴

—(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —CH₂—CH(CH₃)—, —CH₂—CH(CH₂—CH₃)—,—CH₂—CHOR¹⁰—CH₂—;

R⁹ C₁-C₂₄-alkyl;

R¹⁰ hydrogen, C₁-C₂₄-alkyl, R⁹—C(═O)—;

n 1 to 8;

s 0;

u 1 to 5000;

v 0 to 5000;

w 0 to 5000.

The polymers particularly preferably used are obtainable bypolymerization of

a) at least one vinyl ester of aliphatic C₁-C₁₂-carboxylic acids, in thepresence of

b) polyethers of the general formula I with a number average molecularweight of from 300 to 100,000, in which the variables have,independently of one another, the following meanings:

R¹ hydrogen, C₁-C₁₂-alkyl, polyalcohol residue;

R⁸ hydrogen, C₁-C₁₂-alkyl;

R² to R⁴

—(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —CH₂—CH(CH₃)—, —CH₂—CH(CH₂—CH₃)—,—CH₂—CHOR¹⁰—CH₂—;

R¹⁰ hydrogen, C₁-C₁₂-alkyl;

n 1 to 5;

s 0;

u 2 to 2000;

v 0 to 2000;

w 0 to 2000.

The polymers very particularly preferably used are obtainable bypolymerization of

a) at least one vinyl ester of aliphatic C₁-C₆-carboxylic acids, inparticular vinyl acetate, in the presence of

b) polyethers of the general formula I with a number average molecularweight of from 500 to 20,000, in which the variables have, independentlyof one another, the following meanings:

R¹, R⁸

hydrogen, C₁-C₆-alkyl, in particular hydrogen;

R² to R⁴

—(CH₂)₂—, —(CH₂)₃—, —CH₂—CH(CH₃)—, —CH₂—CHOR¹⁰—CH₂—, in particular—(CH₂)₂—;

R¹⁰ hydrogen, C₁-C₆-alkyl;

n 1;

s 0;

u 5 to 500;

v 0 to 500, in particular 0;

w 0 to 500, in particular 0.

Component a) which may be mentioned for polymerization in the presenceof polyethers of the formula I comprises the following copolymerizablemonomers:

vinyl esters of aliphatic, saturated or unsaturated C₁-C₂₄-carboxylicacids, such as, for example, formic acid, acetic acid, propionic acid,butyric acid, valeric acid, isovaleric acid, caproic acid, caprylicacid, capric acid, undecylenic acid, lauric acid, myristic acid,palmitic acid, palmitoleic acid, stearic acid, oleic acid, arachic acid,behenic acid, lignoceric acid, cerotic acid and melissic acid.

Vinyl esters of the abovementioned C₁-C₁₂-carboxylic acids, inparticular the C₁-C₆-carboxylic acids, are preferably used.

It is, of course, also possible for mixtures of the respective monomersin group a) to be graft copolymerized.

The hydrophobic monomers may moreover be employed mixed with one or morelikewise hydrophobic comonomers, for example esters which are difficultto hydrolyze of unsaturated carboxylic acids and/or alkyl ethers, itbeing necessary to restrict the maximum content of these additionalmonomers to 30%. Contents of from 1 to 20% are preferred.

Additional monomers which can be employed for the polymerization interalia comprise at least one other component c) selected from the group of

c₁) C₁-C₂₄-alkyl esters of monoethylenically unsaturatedC₃-C₈-carboxylic acids;

c₂) C₁-C₂₄-hydroxyalkyl esters of monoethylenically unsaturatedC₃-C₈-carboxylic acids;

c₃) C₁-C₂₄-alkyl vinyl ethers;

c₄) N-vinyllactams;

c₅) monoethylenically unsaturated C₃-C₈-carboxylic acids.

A suitable monoethylenically unsaturated C₃-C₈-carboxylic acid isacrylic acid, methacrylic acid, maleic acid, fumaric acid, itaconic acidor aconitic acid.

Alkyl radicals which may be mentioned are branched or unbranchedC₁-C₂₄-alkyl chains, preferably methyl, ethyl, n-propyl, 1-methylethyl,n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl,1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl,1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, n-heptyl, 2-ethylhexyl,n-octyl, n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tridecyl,n-tetradecyl, n-pentadecyl, n-hexadecyl, n-heptadecyl, n-octadecyl,n-nonadecyl or n-eicosyl and the hydroxylated derivatives thereof.

Branched or unbranched C₁-C₄-alkyl chains are preferred, in particularmethyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl,2-methylpropyl, 1,1-dimethylethyl and the hydroxylated derivativesthereof.

Particularly preferred monomers c₁-c₃) are methyl (meth)acrylate, ethyl(meth)acrylate, hydroxymethyl (meth)acrylate, 2-hydroxyethyl(meth)acrylate, methyl vinyl ether and ethyl vinyl ether.

The hydrophobic monomers may moreover be employed mixed with one or morehydrophilic comonomers. Those which can be used are monoethylenicallyunsaturated C₃-C₈-carboxylic acids such as acrylic acid, methacrylicacid, maleic acid, fumaric acid, itaconic acid, aconitic acid, as wellas N-vinyllactams such as N-vinylpyrrolidone, N-vinylimidazole orN-vinylcaprolactam.

Preferred hydrophilic comonomers are (meth)acrylic acid andN-vinylpyrrolidone.

The K values of the polymers should be in the range from 10 to 200,preferably 15 to 150, particularly preferably 15 to 100, veryparticularly preferably in the range from 20 to 80. The K value desiredin each case can be adjusted in a manner known per se by the compositionof the starting materials. The K values are determined by the method ofFikentscher, Cellulosechemie, Vol. 13, pp. 58 to 64 and 71 to 74 (1932)in N-methylpyrrolidone at 25° C. and polymer concentrations between 0.1%by weight and 5% by weight, depending on the K value range.

The polymers can be prepared by polymerizing the monomers of componenta) in the presence of the polyethers by using initiators which form freeradicals and by the action of high-energy radiation, which is to beunderstood to include the action of high-energy electrons.

The polymerization can be, for example, a solution polymerization, bulkpolymerization, emulsion polymerization, inverse emulsionpolymerization, suspension polymerization, inverse suspensionpolymerization or precipitation polymerization, without the methodswhich can be used being restricted thereto.

The procedure for the bulk polymerization, which is preferred, can besuch that the polyalkylene oxide is dissolved in at least one monomer ofgroup a) and, after addition of a polymerization initiator, the mixtureis completely polymerized. The graft copolymerization can also becarried out semicontinuously by firstly mixing part, e.g. 10%, of themixture to be polymerized consisting of polyalkylene oxide, at least onemonomer of group a) and initiator, heating the mixture to thepolymerization temperature and, after the polymerization has started,adding the remainder of the mixture to be polymerized as thepolymerization proceeds. The graft copolymers can also be obtained byintroducing the polyalkylene oxides of group b) into a reactor andheating to the polymerization temperature, and adding at least onemonomer of group a) and polymerization initiator, either all at once,batchwise or, preferably, continuously, and polymerizing.

The ratio of the amounts of the polyethers used as grafting base and thevinyl esters employed is in the range from 1:0.5 to 1:50, preferably inthe range from 1:1.5 to 1:35, particularly preferably in the range from1:2 to 1:30.

Particularly suitable polymerization initiators are organic peroxidessuch as diacetyl peroxide, dibenzoyl peroxide, succinyl peroxide,di-tert-butyl peroxide, tert-butyl perbenzoate, tert-butyl perpivalate,tert-butyl permaleate, cumene hydroperoxide, diisopropylperoxydicarbonate, bis(o-toluoyl) peroxide, didecanoyl peroxide,dioctanoyl peroxide, dilauroyl peroxide, tert-butyl perisobutyrate,tert-butyl peracetate, di-tert-amyl peroxide, tert-butyl hydroperoxide,and mixtures of said initiators, redox initiators and azo initiators.

The amounts used of the initiator or initiator mixtures are, based onmonomer employed, between 0.01 and 10% by weight, preferably between 0.3and 5% by weight.

The graft copolymerization takes place at a temperature in the rangefrom 40 to 200° C., preferably in the range from 50 to 140° C.,particularly preferably in the range from 60 to 110° C. It is normallycarried out under atmospheric pressure, but may also take place underreduced or elevated pressure, preferably between 1 and 5 bar.

If required, the graft copolymerization described above can also becarried out in a solvent. Examples of suitable solvents are alcoholssuch as methanol, ethanol, n-propanol, isopropanol, n-butanol,sec-butanol, tert-butanol, n-hexanol and cyclohexanol, and glycols suchas ethylene glycol, propylene glycol and butylene glycol, and the methylor ethyl ethers of the dihydric alcohols, diethylene glycol, triethyleneglycol, glycerol and dioxane. The graft copolymerization can also becarried out in water as solvent. In this case, a solution which,depending on the amount of added monomers of component a), is more orless readily soluble in water is initially present. In order to convertwater-insoluble products, which may arise during the polymerization,into a solution, it is possible, for example, to add organic solventssuch as monohydric alcohols having 1 to 3 carbon atoms, acetone ordimethylformamide. However, the procedure for graft copolymerization inwater can also be such that the water-insoluble graft copolymers areconverted into a fine-particle dispersion by adding conventionalemulsifiers or protective colloids, e.g. polyvinyl alcohol.

The emulsifiers used are, for example, ionic or nonionic surfactantswhose HLB is in the range from 3 to 13. For the definition of HLB,reference is made to the publication by W. C. Griffin, J. Soc. CosmeticChem., Volume 5, 249 (1954).

The amount of surfactants, based on the graft copolymer, is from 0.1 to5% by weight. Solutions or dispersions of the graft copolymers areobtained on use of water as solvent. Where solutions of the graftcopolymer in an organic solvent or in mixtures of an organic solvent andwater are prepared, from 5 to 200, preferably 10 to 100, parts by weightof organic solvent or of the solvent mixture are used per 100 parts byweight of the graft copolymer.

To increase the hydrophilicity of the polymers used according to theinvention, ester groups can be (partially) hydrolyzed after thepolymerization. The hydrolysis takes place in a manner known per se byadding a base, preferably by adding a methanolic solution of sodium orpotassium hydroxide at temperatures in the range from 10 to 50° C.,preferably in the range from 15 to 30° C. The degree of hydrolysisdepends on the amount of base employed, on the hydrolysis temperatureand on the hydrolysis time.

The degree of hydrolysis of the polyvinyl ester groups can thus be inthe range from 0 to 100%. It is preferably in the range from 20 to 100%,particularly preferably in the range from 40 to 100%, especially from 65to 100% and very particularly preferably in the range from 80 to 100%.

The solids content of the resulting aqueous polymer dispersions orsolutions is usually from 10 to 70% by weight, preferably 15 to 65% byweight, particularly preferably 20 to 60% by weight.

Depending on the degree of hydrolysis and the concentration, aqueousdispersions or solutions of the polymers used according to the inventionare obtained with a viscosity of less than 1000 mPas, preferably with aviscosity of from 5 to 400 mPas, particularly preferably from 10 to 250mPas, at a polymer concentration of 20% by weight.

The polymer dispersions or solutions can be converted into powder formby various drying processes such as spray drying, fluidized spraydrying, drum drying or freeze-drying. Spray drying is preferablyemployed as drying process owing to the advantageous low viscosity ofthe polymer solutions or dispersions. An aqueous dispersion or solutioncan be prepared anew from the resulting dry polymer powder byredispersion in water. Conversion into powder form has the advantagethat storability is improved, transportability is simpler and thetendency to be attacked by microbes is reduced.

The water-soluble or water-dispersible polyalkylene oxide orpolyglycerol-containing polymers are outstandingly suitable as filmformer, binder, wetting aid and/or solubilizer, which is soluble ordispersible in gastric fluid, for pharmaceutical presentations.

The exceptional flexibility and the low viscosity means that noadditional plasticizer is usually necessary.

The invention therefore also relates to pharmaceutical presentationscomprising at least one water-soluble or water-dispersible polymer ascoating agent, binder and/or film-forming excipient, the polymer beingobtainable by polymerization of

a) at least one vinyl ester of aliphatic C₁-C₂₄-carboxylic acids in thepresence of

b) polyethers of the general formula I,

 in which the variables have, independently of one another, thefollowing meanings:

R¹ hydrogen, C₁-C₂₄-alkyl, R⁹—C(═O)—, R⁹—NH—C(═O)—, polyalcohol residue;

R⁸ hydrogen, C₁-C₂₄-alkyl, R⁹—C(═O)—, R⁹—NH—C(═O)—;

R² to R⁷

—(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —CH₂—CH(CH₃)—, —CH₂—CH(CH₂—CH₃)—,—CH₂—CHOR¹⁰—CH₂—;

R⁹ C₁-C₂₄-alkyl;

R¹⁰ hydrogen, C₁-C₂₄-alkyl, R⁹—C(═O)—;

A —C(═O)—O—, —C(═O)—B—C(═O)—O—, —C(═O)—NH—B—NH—C(═O)—O—;

B —(CH₂)_(t)—, arylene, optionally substituted;

n 1 to 8;

s 0 to 500;

t 1 to 12;

u 1 to 5000;

v 0 to 5000;

w 0 to 5000;

x 1 to 5000;

y 0 to 5000;

z 0 to 5000.

For a more detailed illustration of the graft copolymers, including thevariables and the preferred embodiments thereof, reference may be madeto the description given at the outset.

The coated presentations are preferably inter alia film-coated tablets,film-coated microtablets, sugar-coated tablets, coated pastilles,capsules, crystals, granules or pellets.

The binder-containing presentations are preferably inter alia tablets,microtablets, cores, granules or pellets.

The polymers according to the invention can also be used to producesolutions and sprays which, applied to the skin or mucous membrane, forma film. Owing to the exceptional elasticity and adhesiveness, the filmsadhere for a long time to the skin or mucous membrane. The frequency ofapplication can thus be reduced, and the comfort of wearing isincreased. Examples thereof are spray-on dressings for wounds,disinfectant sprays, solutions with mycostatics, sprays or solutions forthe mouth with antibiotics etc. The flexibility also means that use fortransdermal therapeutic systems is advantageous.

The graft copolymers used according to the invention easily wetlipophilic surfaces and have excellent protective colloid properties.Incorporated into suspensions and emulsions, they attach themselves tothe particles of the disperse phase and stabilize it. They can thereforebe used as wetting aids and stabilizers in disperse systems.

They improve the solubility and rate of dissolution of medicinalsubstances of low solubility in water by interacting with them, wherebythe absorbability and bioavailability of the medicinal substances areimproved. This advantageous effect is evident, for example, withpresentations in which the active ingredient is not present in solution,such as, for example, tablets, granules, suspensions etc.

The polymers used according to the invention can, where appropriate alsoin combination with other excipients, be processed together with activeingredients to polymer/active ingredient melts which either undergoextrusion and calendering to give drug products or, after the extrusion,are converted into granules or powders and only then processed to drugforms, for example compressed to tablets. In these cases, the graftcopolymers introduce the properties detailed above into thepresentation.

The polymers according to the invention are able to fulfil the followingfunctions in an outstanding manner in various pharmaceuticalpresentations:

dispersing aid, suspending aid, wetting agent, solubilizer for medicinalsubstances of low solubility, emulsifier, crystallization inhibitor,anticaking aid, protective colloid, bioadhesive to prolong and intensifycontact with the mucous membrane, spreading aid, viscosity regulator,excipient for producing solid solutions with medicinal substances,excipient for adjusting the release of active ingredient in slow releaseformulations.

The polymers according to the invention which are of only low solubilityor insoluble but dispersible in water can also be used asrelease-slowing polymers and as adhesives for active ingredientplasters.

When used to produce suppositories and pessaries, the polymers on theone hand ensure the flexibility of the presentation, and on the otherhand promote the disintegration and dissolution of active ingredient,and they coat the mucous membrane with an active ingredient-containingfilm which enhances absorption.

As shown in Table 1, the aqueous solutions of the (partly) hydrolyzedpolymers according to the invention have a distinctly lower viscositythan corresponding solutions of hydroxypropylmethylcellulose.

TABLE 1 Viscosity (20% by weight Flexibility aqueous solution) Ultimateelongation Polymer [mPas] [%] PEG 6000/VAc 124 74 (Example 1) PEG6000/VAc 181 172 (Example 2) PEG 9000/VAc 199 225 (Example 3)Polyglycerol 2200/VAc 199 313 (Example 4) Lutrol ® F 68/VAc 145 110(Example 5) PEG 6000/VAc/MMA 144 122 (Example 6) Pharmacoat ® 606 516815 (Comparison)

It is thus possible to employ more concentrated polymer preparationswhen coating tablets with the polymer dispersions, as well as for binderapplications, which allows the processes to be made considerably morecost effective and time-saving.

The dissolution or redispersion of the polymers in powder or granuleform to aqueous dispersions or solutions takes place considerably morequickly than with other film formers or binders, because the polymersaccording to the invention are thoroughly wetted by water and showlittle agglomeration and a very high dissolution rate.

Gastric fluid-soluble tablets coated with the (partly) hydrolyzedpolymers according to the invention show a disintegration time which isonly slightly longer than for the core, i.e. the film coating dissolvesvery rapidly in simulated gastric fluid.

In the case of the Pharmacoat 606 type of hydroxypropylmethylcelluloseas coating material, disintegration takes distinctly longer (seeExamples 7 and 8 with their respective comparative examples). Inaddition, the mechanical strength of the tablets is increased very muchmore when the polymers are used according to the invention than whenhydroxypropylmethylcellulose is used.

Tablets swell to different extents depending on the excipients andactive ingredients used, the storage time and the storage conditions,such as temperature and humidity. A rigid film coating develops crackswhen the core swells. The elasticity of film formers is therefore animportant quantity. Graft copolymers have exceptionally high flexibilityand elasticity. Thus, the ultimate elongation may be up to 300%. Nocrack formation is therefore to be expected, even if the core swellsgreatly.

The graft copolymers can be applied in pure form or else together withconventional excipients to the active ingredient-containing core.Examples of conventional excipients are colored pigments for coloring,white pigments such as titanium dioxide to increase the hiding power,talc and silicon dioxide as non-stick agents, polyethylene glycols,glycerol, propylene glycol, triacetin, triethyl citrate as plasticizerand various surface-active substances such as sodium lauryl sulfate,polysorbate 80, Pluronics and Cremophors, to improve the wettingcharacteristics. The substances mentioned as examples do not represent arestriction. All additives known to be suitable for gastricfluid-soluble film coatings can be used.

It is also possible to combine the polymers used according to theinvention with other film formers or polymers in the ratio from 1:9 to9:1.

Examples of polymers which can be employed for this purpose are thefollowing:

polyvinylpyrrolidone, polyvinylpyrrolidone copolymers, water-solublecellulose derivatives such as hydroxypropylcellulose,hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose,acrylate and methacrylate copolymers, polyvinyl alcohols, polyethyleneglycols, polyethylene oxide/polypropylene oxide block copolymers.

The coating processes which can be used are the conventional processessuch as coating in a fluidized bed or in a horizontal drum coater, thedip-coating process and the pan-coating process. Besides the use fortablets, the polymers according to the invention can also be employedfor coating other pharmaceutical preparations such as granules, pellets,crystals or capsules. The novel coating agents are applied in aconventional manner in a thickness of from 5 to 200 μm, preferably 10 to100 μm.

In the use as binder, a distinction is made between wet and dry bindersdepending on the processing method. The latter are used inter alia fordirect tableting and for dry granulation or compaction. In these cases,the binder is mixed with the active ingredient and, where appropriate,other excipients and then directly tableted, or granulated andcompacted.

In contrast thereto, in wet granulation the active ingredient/excipientmixture is moistened with a solution of the binder in water or anorganic solvent and the moist composition is passed through a sieve andthen dried. The moistening and drying may also take place in parallelas, for example, in fluidized bed granulation.

For optimal processing, the binder should have a low viscosity insolution because viscous solutions lead to inhomogeneous granules.

A binder should lead to uniform, hard, non-friable granules or tablets.The hardness is particularly important for tablets because many activeingredients are difficult to compress and thus afford tablets withinadequate mechanical stability.

In addition, the binder should have a negligible adverse effect on thedisintegration of the drug forms and the rate of release of the activeingredients.

The most commonly used binders are, for example, polyvinylpyrrolidone,vinyl acetate/vinylpyrrolidone copolymers, gelatin, starch pastes,maltodextrins, hydroxyalkylated or carboxyalkylated cellulosederivatives such as hydroxypropylmethylcellulose, methylcellulose,sodium carboxymethylcellulose, and natural gum types such as, forexample, gum arabic, pectin or alginate.

Many of these binders have a high viscosity in solution and aredifficult to process. The high viscosity means that the powder particlesto be granulated are poorly and non-uniformly wetted, resulting in agranule strength which is too low and a particle size distribution whichis unfavorable.

Many binders are, moreover, hygroscopic and swell on absorption ofwater. This may drastically alter the properties of granules andtablets.

It has now been found, surprisingly, that the polymers according to theinvention have excellent effects as binders and, moreover, have anegligible effect on disintegration in concentration ranges from 0.5 to20% by weight, preferably 1 to 10% by weight, of the total amount of theformulation. Because the graft copolymers have good wettingcharacteristics, it is moreover possible to improve the release ofactive ingredients of low solubility.

When the graft copolymers are used as binders, the resulting granulesand tablets are exceptionally mechanically stable and also stable onstorage for long periods.

The invention also relates to polymers which are obtainable bypolymerization of

a) at least one vinyl ester of aliphatic C₁-C₂₄-carboxylic acids in thepresence of

b) polyethers of the general formula I,

 in which the variables have, independently of one another, thefollowing meanings:

R¹ hydrogen, C₁-C₂₄-alkyl, R⁹—C(═O)—, polyalcohol residue;

R⁸ hydrogen, C₁-C₂₄-alkyl, R⁹—C(═O)—;

R² to R⁷

—(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —CH₂—CH(CH₃)—, —CH₂—CH(CH₂—CH₃)—,—CH₂—CHOR¹⁰—CH₂—;

R⁹ C₁-C₂₄-alkyl;

R¹⁰ hydrogen, C₁-C₂₄-alkyl, R⁹—C(═O)—;

A —C(═O)—O—, —C(═O)—B—C(═O)—O—;

B —(CH₂)_(t)—, arylene, optionally substituted;

n 1 to 8;

s 1 to 500;

t 1 to 12;

u 1 to 5000;

v 0 to 5000;

w 0 to 5000;

x 1 to 5000;

y 0 to 5000;

z 0 to 5000.

The invention moreover relates to polymers which are obtainable bypolymerization of

a) at least one vinyl ester of aliphatic C₁-C₂₄-carboxylic acids in thepresence of

b) polyethers of the general formula Ia,

R¹OR²—O)uR³—O)_(v)R⁴—O)_(w)—R⁸)_(n)  Ia

 in which the variables have, independently of one another, thefollowing meanings:

R¹ hydrogen, C₁-C₂₄-alkyl, R⁹—C(═O)—, polyalcohol residue;

R⁸ hydrogen, C₁-C₂₄-alkyl, R⁹—C(═O)—;

R² to R⁴

—(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —CH₂—CH(CH₃)—, —CH₂—CH(CH₂—CH₃)—;

R⁹ C₁-C₂₄-alkyl;

n 1 to 8;

u 1 to 5000;

v 0 to 5000;

w 0 to 5000

together with

c) at least one monomer, selected from the group of

c₁) C₁-C₂₄-alkyl esters of monoethylenically unsaturatedC₃-C₈-carboxylic acids;

c₂) C₁-C₂₄-hydroxyalkyl esters of monoethylenically unsaturatedC₃-C₈-carboxylic acids;

c₃) C₁-C₂₄-alkyl vinyl ethers;

c₄) N-vinyllactams;

c₅) monoethylenically unsaturated C₃-C₈-carboxylic acids.

Preferred polymers are obtainable by polymerization of

a) at least one vinyl ester of aliphatic C₁-C₁₂-carboxylic acids in thepresence of

b) polyethers of the general formula Ia, in which the variables have,independently of one another, the following meanings:

R¹ hydrogen, C₁-C₁₂-alkyl, polyalcohol residue;

R⁸ hydrogen, C₁-C₁₂-alkyl;

R² to R⁴

—(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —CH₂—CH(CH₃)—, —CH₂—CH(CH₂—CH₃)—;

n 1 to 5;

u 2 to 2000;

v 0 to 2000;

w 0 to 2000

together with

c) at least one monomer selected from the group of

c₁) C₁-C₁₂-alkyl esters of monoethylenically unsaturatedC₃-C₈-carboxylic acids;

c₂) C₁-C₁₂-hydroxyalkyl esters of monoethylenically unsaturatedC₃-C₈-carboxylic acids;

c₃) C₁-C₁₂-alkyl vinyl ethers;

c₄) N-vinyllactams;

c₅) monoethylenically unsaturated C₃-C₈-carboxylic acids.

Very particularly preferred graft copolymers are obtainable by graftingof

a) at least one vinyl ester of aliphatic C₁-C₆-carboxylic acids in thepresence of

b) polyethers of the general formula Ia, in which the variables have,independently of one another, the following meanings:

R¹ and R⁸

hydrogen, C₁-C₆-alkyl;

R² to R⁴

—(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —CH₂—CH(CH₃)—, —CH₂—CH(CH₂—CH₃)—;

n 1;

u 2 to 500;

v 0 to 500;

w 0 to 500

together with

c) at least one monomer selected from the group of

c₁) C₁-C₆-alkyl esters of monoethylenically unsaturated C₃-C₆-carboxylicacids;

c₄) N-vinylpyrrolidone, N-vinylimidazole, N-vinylcaprolactam;

c₅) (meth)acrylic acid.

The invention likewise relates to polymers which are obtainable bypolymerization of

a) at least one vinyl ester of aliphatic C₁-C₂₄-carboxylic acids in thepresence of

b) polyglycerol of the general formula Ib,

R¹OCH₂—CHOR¹⁰—CH₂—O)_(u)—R⁸)_(n)  Ib

 in which the variables have, independently of one another, thefollowing meanings:

R¹ hydrogen, C₁-C₂₄-alkyl, R⁹—C(═O)—, polyalcohol residue;

R⁸ and R¹⁰

hydrogen, C₁-C₂₄-alkyl, R⁹—C(═O)—;

R⁹ C₁-C₂₄-alkyl;

n 1 to 8;

u 1 to 2000.

Preferred polymers are obtainable by polymerization of

a) at least one vinyl ester of aliphatic C₁-C₁₂-carboxylic acids in thepresence of

b) polyglycerol of the general formula Ib, in which the variables have,independently of one another, the following meanings:

R¹ hydrogen, C₁-C₁₂-alkyl, polyalcohol residue;

R⁸ and R¹⁰

hydrogen, C₁-C₁₂-alkyl;

n 1 to 5;

u 1 to 500.

Particularly preferred polymers are obtainable by polymerization of

a) at least one vinyl ester of aliphatic C₁-C₆-carboxylic acids in thepresence of

b) polyglycerol of the general formula Ib, in which the variables have,independently of one another, the following meanings:

R¹, R⁸ and R¹⁰

hydrogen, C₁-C₆-alkyl;

n 1;

u 1 to 100.

Besides the linear polyglycerols of the general formula II, it is alsopossible to use branched and/or cyclic polyglycerols as grafting base.

The graft copolymers based on polyglycerol can be prepared by using forthe grafting, in addition to the vinyl esters, at least one othermonomer c) selected from the group of

c₁) C₁-C₂₄-alkyl esters of monoethylenically unsaturatedC₃-C₈-carboxylic acids;

c₂) C₁-C₂₄-hydroxyalkyl esters of monoethylenically unsaturatedC₃-C₈-carboxylic acids;

c₃) C₁-C₂₄-alkyl vinyl ethers;

c₄) N-vinyllactams;

c₅) monoethylenically unsaturated C₃-C₈-carboxylic acids.

Preferred monomers c) are C₁-C₆-alkyl esters of monoethylenicallyunsaturated C₃-C₈-carboxylic acids, N-vinylpyrrolidone,N-vinylimidazole, N-vinylcaprolactam and (meth)acrylic acid.

For a detailed illustration of the graft copolymers based on polyethersof the formula Ia and based on polyglycerol of the formula Ib, includingthe preferred embodiments, reference may be made to the descriptiongiven at the outset.

The production and use of the graft copolymers according to theinvention are illustrated in detail in the following examples without,however, restricting the invention to the examples.

Preparation of the Graft Copolymers

EXAMPLE 1

72 g of polyethylene glycol (average molecular weight 6000, Pluriol® E6000) were introduced into a polymerization vessel and heated to 80° C.with stirring under a gentle stream of nitrogen. While stirring andmaintaining at 80° C., 410 g of vinyl acetate were added dropwise overthe course of 3 h and, at the same time, a solution of 1.4 g oftert-butyl perpivalate in 30 g of methanol was added dropwise, likewiseover the course of 3 h. After the addition was complete, the mixture wasstirred at 80° C. for 2 h. After cooling, the polymer was dissolved in450 ml of methanol. For the hydrolysis, 50 ml of a 10% strengthmethanolic sodium hydroxide solution were added at 30° C. After about 40min., the reaction was stopped by adding 750 ml of 1% strength aceticacid. The solution was steam distilled to remove the methanol. The clearsolution was then freeze dried to result in a white powder. A 20%aqueous solution of the resulting polymer had a viscosity of 124 mPas.The K value was 54, and the ultimate elongation was 74%.

EXAMPLE 2

30 g of polyethylene glycol (average molecular weight 6000, Pluriol® E6000) were introduced into a polymerization vessel and heated to 80° C.with stirring under a gentle stream of nitrogen. While stirring andmaintaining at 80° C., 570 g of vinyl acetate were added dropwisesimultaneously with a solution of 2 g of tert-butyl perpivalate in 45 gof methanol over the course of 3 h. After the addition was complete, themixture was stirred at 80° C. for 2 h. After cooling, the polymer wasdissolved in 550 ml of methanol. For the hydrolysis, 65 ml of a 10% byweight methanolic sodium hydroxide solution were added at 30° C. Afterabout 40 min, the reaction was stopped by adding 500 ml of 1% strengthacetic acid. The solution was steam distilled to remove the methanol.The clear solution was then freeze dried to result in a white powder. A20% by weight aqueous solution of the resulting polymer had a viscosityof 46 mPas. The K value was 73, and the ultimate elongation was 171%.

EXAMPLE 3

100 g of polyethylene glycol (average molecular weight 9000) wereintroduced into a polymerization vessel and heated to 80° C. withstirring under a gentle stream of nitrogen. While stirring andmaintaining at 80° C., 300 g of vinyl acetate were added dropwisesimultaneously with a solution of 1.5 g of tert-butyl perpivalate in 30ml of methanol over the course of 3 h. After the addition was complete,polymerization was continued at 80° C. for 2 h. After cooling, thepolymer was dissolved in 400 ml of methanol. For the hydrolysis, 40 mlof a 10% by weight methanolic sodium hydroxide solution were added at30° C. After about 40 min., the reaction was stopped by adding 550 ml of1% strength acetic acid. The solution was steam distilled to remove themethanol. The clear solution was then freeze dried to result in a whitepowder. A 20% by weight aqueous solution of the resulting polymer had aviscosity of 199 mPas. The K value was 58, and the ultimate elongationwas 225%.

EXAMPLE 4

60 g of polyglycerol (average molecular weight 2200) were introducedinto a polymerization vessel and heated to 80° C. with stirring under agentle stream of nitrogen. While stirring and maintaining at 80° C., 340g of vinyl acetate were added dropwise simultaneously with a solution of1.2 g of tert-butyl perpivalate in 30 ml of methanol over the course of3 h. After the addition was complete, polymerization was continued at80° C. for 2 h. After cooling, the polymer was dissolved in 400 ml ofmethanol. For the hydrolysis, 40 ml of a 10% by weight methanolic sodiumhydroxide solution were added at 30° C. After about 40 min., thereaction was stopped by adding 640 ml of 1% strength acetic acid. Thesolution was steam distilled to remove the methanol. The clear solutionwas then freeze dried to result in a white powder. A 20% by weightaqueous solution of the resulting polymer had a viscosity of 199 mPas.The K value was 66, and the ultimate elongation was 313%.

EXAMPLE 5

60 g of polyethylene glycol/polypropylene glycol block copolymer(average molecular weight about 8000) were introduced into apolymerization vessel and heated to 80° C. with stirring under a gentlestream of nitrogen. While stirring and maintaining at 80° C., 340 g ofvinyl acetate were added dropwise simultaneously with a solution of 1.2g of tert-butyl perpivalate in 30 ml of methanol over the course of 3 h.After the addition was complete, polymerization was continued at 80° C.for 3 h. After cooling, the polymer was dissolved in 400 ml of methanol.For the hydrolysis, 40 ml of a 10% by weight methanolic sodium hydroxidesolution were added at 30° C. After about 40 min., the reaction wasstopped by adding 650 ml of 1% strength acetic acid. The solution wassteam distilled to remove the methanol. The clear solution was thenfreeze dried to result in a white powder. A 20% by weight aqueoussolution of the resulting polymer had a viscosity of 145 mPas. The Kvalue was 45, and the ultimate elongation was 110%.

EXAMPLE 6

60 g of polyethylene glycol (average molecular weight about 6000) wereintroduced into a polymerization vessel and heated to 80° C. withstirring under a gentle stream of nitrogen. While stirring andmaintaining at 80° C., 332 g of vinyl acetate and 8 g of methylmethacrylate were added dropwise over the course of 3 h and, at the sametime, a solution of 1.2 g of tert-butyl perpivalate in 30 ml of methanolwas added dropwise, likewise over the course of 3 h. After the additionwas complete, polymerization was continued at 80° C. for 2 h. Aftercooling, the polymer was dissolved in 400 ml of methanol. For thehydrolysis, 40 ml of a 10% by weight methanolic sodium hydroxidesolution were added at 30° C. After about 40 min., the reaction wasstopped by adding 600 ml of 1% strength acetic acid. The solution wassteam distilled to remove the methanol. The clear solution was thenfreeze dried to result in a white powder. A 20% strength aqueoussolution of the resulting polymer had a viscosity of 144 mPas. The Kvalue was 56, and the ultimate elongation was 122%.

EXAMPLE 7

Production of propranolol HCl film-coated tablets (coating soluble ingastric fluid)

A film coating of the following composition

PEG 6000/VAc graft 10.0% by weight  copolymer from Example 1 Sicovit ®red (from 1.5% by weight BASF AG) Titanium dioxide BN 3.0% by weight 56(from Kronos) Talcum powder (from 4.5% by weight Riedel de Haen) Water81.0% by weight 

was sprayed onto 9 mm biconvex tablet cores containing 40 mg ofpropranolol HCl (from Knoll AG), 195.0 mg of Ludipress® (from BASF AG),12.50 mg of Kollidon® VA 64 (from BASF AG) and 2.50 mg of magnesiumstearate in a horizontal drum coater (Accela-Cota 24″, from Manesty).

The spray dispersion was prepared by dissolving the graft copolymer inwater, adding Sicovit® red, titanium dioxide and talcum and subsequentlyhomogenizing in a corundum disk mill. 1260 g (including a 10% overagefor spray losses) were applied to 5000 g of cores using a spray nozzlewith a width of 1.0 mm under a pressure of 2.0 bar and with an inlet airtemperature of 60° C. and a spraying rate of 30 g/min. The spraying wasfollowed by drying at 60° C. for 5 min.

The resulting red film-coated tablets were very smooth and glossy andhad the following properties:

Appearance: very smooth surface, imprint nicely formed

Disintegration (sim. gastric fluid): 5 min. 26 s.

Difference in disintegration times (film-coated tablet/core): 57 s.

Hardness: 92 N

Difference in hardness (film-coated tablet/core): 23 N

COMPARATIVE EXAMPLE

In analogy to Example 7, Pharmacoat® 606 (hydroxypropylmethylcellulose,from Shin-etsu) was employed in place of the graft copolymer and, asrecommended by the manufacturer, 1.0% by weight of polyethylene glycol6000 (Lutrol® 6000, BASF AG) was added.

Tablets with the following properties were obtained:

Appearance: slightly rough surface, blurred imprint

Disintegration (sim. gastric fluid): 11 min. 12 s.

Difference in disintegration times (film-coated tablet/core): 6 min. 43s.

Hardness: 87 N

Difference in hardness (film-coated tablet/core): 18 N

EXAMPLE 8

A methyl-PEG 1500/VAc graft copolymer (prepared as in Example 1) wasprocessed as in Example 7. The spray solution used had the followingcomposition:

Methyl-PEG 1500/VAc 20.0% by weight  Sicovit ® red (from 1.5% by weightBASF AG) Titanium dioxide BN 3.0% by weight 56 (from Kronos) Talcumpowder 4.5% by weight (from Riedel de Haen) Water 71.0% by weight 

Once again, smooth, slightly glossy, red film-coated tablets wereobtained.

Appearance: smooth surface, nicely formed imprint

Disintegration (sim. gastric fluid): 5 min. 35 s.

Difference in disintegration times (film-coated tablet/core): 1 min. 06s.

Hardness: 94 N

Difference in hardness (film-coated tablet/core): 25 N

COMPARATIVE EXAMPLE

Pharmacoat® 606 was employed in place of methyl-PEG 1500/VAc in analogyto Example 8. It was impossible to spray the solution on because of theextremely high viscosity of Pharmacoat® 606.

EXAMPLE 9

Use as Binder in Glibenclamide Tablets

890 g of calcium hydrogenphosphate (from Rhone Poulenc) and 30 g ofglibenclamide (from Arzneimittelwerk Dresden) were passed through a 0.8mm sieve and mixed in a Turbula mixer (from Bachofen) for 5 min. Thispowder mixture was moistened slowly with 119 g of a 25% by weightaqueous preparation of a PEG 1500/VAc graft copolymer (prepared as inExample 2) while stirring in a Stephan mixer (from Stephan). To completethe moistening, stirring was continued at 800 rpm for 2 min afteraddition of the binder preparation. The moist composition was thenpassed through a 0.8 mm sieve and dried on a tray at 25° C. for 20 h.Addition of 45 g of Kollidon® CL (from BASF) and 5 g of magnesiumstearate (from Bärlocher) was followed by final mixing once again in aTurbula mixer for 5 min. This tabletting mixture was then compressed tobiplanar, beveled tablets with a diameter of 12 mm and a total weight of500 mg in a Korsch PH 106 rotary press (from Korsch) under a force of 10kN and 18 kN.

Properties: Force 10 kN Force 18 kN Hardness: 28 N 53 N Friability: 0.7%0% Disintegration: 29 s. 37 s.

COMPARATIVE EXAMPLE

Production took place as in Example 9 but withhydroxypropylmethylcellulose (Pharmacoat® 603, from Shin-etsu) asbinder, it being necessary for viscosity reasons to reduce theconcentration of the binder in the solution to 20% by weight.

Properties: Force 10 kN Force 18 kN Hardness: 16 N 40 N Friability: 8.0%0.6% Disintegration: 35 s. 58 s.

EXAMPLE 10

Use as Binder in a Hydrochlorothiazide Tablet

A mixture of 8950 g of fine lactose (from Meggle), 350 g ofhydrochlorothiazide (from Chemag) and 350 g of Kollidon® CL (from BASF)is sprayed in a WSG 15 fluidized bed granulator (from Glatt) with abinder preparation consisting of 350 g of a polyglycerol 2200/VAc graftcopolymer (Example 4) and 3000 g of water, and thus granulated in thefluidized bed.

The settings for the process parameters were as follows:

Inlet air temperature: 90° C. Outlet air temperature 37° C. Sprayingrate 143 g/min Spraying pressure 4 bar

The granulation was followed by drying in the apparatus at 90° C. for2.5 min. The granules were passed through a 0.8 mm sieve, mixed with 5 gof magnesium stearate (from Bärlocher) and mixed in a Turbula mixer(from Bachofen) for 5 min. Tabletting took place in a Korsch PH 106(from Korsch) rotary press under a force of 18 kN to give biplanar,beveled tablets with a diameter of 10 mm and a total weight of 300 mg.

Properties of the granules:

Angle of repose: 30°

Appearance: very uniform, negligible fines

Tablet properties:

Hardness: 186 N

Friability: <0.1%

Disintegration: 4 min. 20 s.

Release in sim. gastric fluid (Ph. Eur.) 92% after 15 min.

COMPARATIVE EXAMPLE

Production took place as in Example 10 but withhydroxypropylmethylcellulose (Pharmacoat® 603, from Shin-etsu) asbinder.

Properties of the granules:

Angle of repose: 33°

Appearance: somewhat inhomogeneous, some relatively large agglomerates

Tablet properties:

Hardness: 175 N

Friability: 0.2%

Disintegration: 5 min. 10 s.

Release in sim. gastric fluid (Ph. Eur.) 82% after 15 min.

EXAMPLE 11

Use as Ancillary Substance to Produce Ultrasonic Gels

5 g of methyl p-hydroxybenzoate were dissolved in 724 g of demineralizedwater at 50° C. Then 6 g of polyacrylic acid (Carbopol® 940, fromGoodrich) and 15 g of a PEG 9000/VAc graft copolymer (Example 3) wereincorporated with stirring. Addition of 200 g of demineralized water and50 g of 4% strength aqueous sodium hydroxide solution was followed bystirring for 15 min, taking care that no air was incorporated. Theresulting gel had a very pleasant skin feel and good contact properties.

EXAMPLE 12

Use as Stabilizer in an Ibuprofen Suspension

250 g of sucrose, 20 g of a Lutrol® F68/VAc graft copolymer (Example 5)and 20 g of sodium citrate were dissolved in demineralized water. Then80 g of crosslinked polyvinylpyrrolidone (Kollidon® CL-M, BASF AG) and40 g of ibuprofen 50 (Knoll AG) were stirred in, and the volume was madeup to 1000 ml with demineralized water. The resulting low-viscosity,homogeneous white suspension showed sedimentation stability and noaggregation or caking over several weeks.

EXAMPLE 13

Use as Film Former in a Disinfectant Spray

150 g of a PEG 6000/VAc graft copolymer (Example 1) were dissolved in375 g of demineralized water, and 375 g of ethanol were added. Then 100g of polyvinylpyrrolidone-iodine (PVP-iodine 30/06, BASF AG) weredissolved with stirring in this polymer solution, and the preparationwas used to fill pump spray bottles. The disinfectant spray showed verygood film properties on the skin and no loss of iodine after storageunder stress conditions (7 days at 52° C.).

We claim:
 1. A pharmaceutical presentation comprising the graft polymersobtained by polymerization of a) at least one vinyl ester of aliphaticC₁-C₂₄-carboxylic acids in the presence of b) polyethers of the generalformula I,

 in which the variables have, independently of one another, thefollowing meanings: R¹ hydrogen, C₁-C₂₄-alkyl, R⁹—C(═O)—, polyalcoholresidue; R⁸ hydrogen, C₁-C₂₄-alkyl, R⁹—C(═O)—; R² to R⁷ —(CH₂)₂—,—(CH₂)₃—, —(CH₂)₄—, —CH₂—CH(CH₃)—, —CH₂—CH(CH₂—CH₃)—, —CH₂—CHOR¹⁰—CH₂—;R⁹ C₁-C₂₄-alkyl; R¹⁰ hydrogen, C₁-C₂₄-alkyl, R⁹—C(═O)—; A —C(═O)—O—,—C(═O)—B—C(═O)—O—, —C(═O)—NH—B—NH—C(═O)—O—; B —(CH₂)_(t)—, arylene,optionally substituted; n 1 to 8; s 0 to 500; u 1 to 5000; v 0 to 5000;w 0 to 5000; x 1 to 5000; y 0 to 5000; z 0 to 5000, wherein themolecular weight of the polyethers is in the range from 300 to 100,000,as coating agent, binder and/or film-forming excipient in pharmaceuticalpresentations.
 2. A pharmaceutical presentation as claimed in claim 1,wherein the graft polymer is obtained by polymerization of a) at leastone vinyl ester of aliphatic C₁-C₁₂-carboxylic acids in the presence ofb) polyethers of the general formula I with a number average molecularweight of from 300 to 100,000, in which the variables have,independently of one another, the following meanings: R¹ hydrogen,C₁-C₁₂-alkyl, polyalcohol residue; R⁸ hydrogen, C₁-C₁₂-alkyl; R² to R⁴—(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —CH₂—CH(CH₃)—, —CH₂—CH(CH₂—CH₃)—,—CH₂—CHOR¹⁰—CH₂—; R¹⁰ hydrogen, C₁-C₁₂-alkyl; n 1 to 5; s 0; u 2 to2000; v 0 to 2000; w 0 to
 2000. 3. A pharmaceutical presentation asclaimed in claim 1, wherein the graft polymer is obtained bypolymerization of a) at least one vinyl ester of aliphaticC₁-C₆-carboxylic acids in the presence of b) polyethers of the generalformula I with a number average molecular weight of from 500 to 20,000,in which the variables have, independently of one another, the followingmeanings: R¹, R⁸ hydrogen, C₁-C₆-alkyl; R² to R⁴ —(CH₂)₂—, —(CH₂)₃—,—CH₂—CH(CH₃)—, —CH₂—CHOR¹⁰—CH₂—; R¹⁰ hydrogen, C₁-C₆-alkyl; n 1; s 0; u5 to 500; v 0 to 500; w 0 to
 500. 4. A pharmaceutical presentation asclaimed in claim 1, wherein, in addition to the vinyl esters a), atleast one other monomer c) selected from the group of c₁) C₁-C₂₄-alkylesters of monoethylenically unsaturated C₃-C₈-carboxylic acids; c₂)C₁-C₂₄-hydroxyalkyl esters of monoethylenically unsaturatedC₃-C₈-carboxylic acids; c₃) C₁-C₂₄-alkyl vinyl ethers; c₄)N-vinyllactams; c₅) monoethylenically unsaturated C₃-C₈-carboxylic acidsis employed for the polymerization.
 5. A pharmaceutical presentation asclaimed in claim 1 having a degree of hydrolysis of from 20 to 100%based on the polyvinyl ester groups.
 6. A pharmaceutical presentation asclaimed in claim 1 having a K value of from 10 to
 200. 7. Awater-soluble or water-dispersible graft polymer which is obtainable bypolymerization of a) at least one vnyl ester of aliphaticC₁-C₂₄-carboxylic acids in the presence of b) polyethers of the generalformula I,

 in which the variables have, independently of one another, thefollowing meanings: R¹ hydrogen, C₁-C₂₄-alkyl, R⁹—C(═O)—, polyalcoholresidue; R⁸ hydrogen, C₁-C₂₄-alkyl, R⁹—C(═O)—; R² to R⁷ —(CH₂)₂—,—(CH₂)₃—, —(CH₂)₄—, —CH₂—CH(CH₃)—, —CH₂—CH(CH₂—CH₃)—, —CH₂—CHOR¹⁰—CH₂—;R⁹ C₁-C₂₄-alkyl; R¹⁰ hydrogen, C₁-C₂₄-alkyl, R⁹—C(═O)—; A —C(═O)—O—,—C(═O)—B—C(═O)—O—; B —(CH₂)_(t)—, arylene, optionally substituted; n 1to 8; s 1 to 500; t 1 to 12; u 1 to 5000; v 0 to 5000; w 0 to 5000; x 1to 5000; y 0 to 5000; z 0 to 5000, wherein the molecular weight of thepolyethers is in the range from 300 to 100,000.
 8. A water-soluble orwater-dispersible graft polymer which is obtained by polymerization ofa) at least one vinyl ester of aliphatic C₁-C₂₄-carboxylic acids in thepresence of b) polyethers of the general formula Ia,R¹OR²—O)_(u)R³—O)_(v)R⁴—O)_(w)—R⁸)_(n)  Ia  in which the variableshave, independently of one another, the following meanings: R¹ hydrogen,C₁-C₂₄-alkyl, R⁹—C(═O)—, polyalcohol residue; R⁸ hydrogen, C₁-C₂₄-alkyl,R⁹—C(═O)—; R² to R⁴ —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —CH₂—CH(CH₃)—,—CH₂—CH(CH₂—CH₃)—; R⁹ C₁-C₂₄-alkyl; n 1 to 8; u 1 to 5000; v 0 to 5000;w 0 to 5000, wherein the molecular weight of the polyethers is in therange from 300 to 100,000, together with c) at least one monomerselected from the group of c₁) C₁-C₂₄-alkyl esters of monoethylenicallyunsaturated C₃-C₈-carboxylic acids; c₂) C₁-C₂₄-hydroxyalkyl esters ofmonoethylenically unsaturated C₃-C₈-carboxylic acids; c₃) C₁-C₂₄-alkylvinyl ethers; c₄) N-vinyllactams; c₅) monoethylenically unsaturatedC₃-C₈-carboxylic acids.
 9. A polymer as claimed in claim 8, which isobtained by polymerization of a) at least one vinyl ester of aliphaticC₁-C₁₂-carboxylic acids in the presence of b) polyethers of the generalformula Ia, in which the variables have, independently of one another,the following meanings: R¹ hydrogen, C₁-C₁₂-alkyl, polyalcohol residue;R⁸ hydrogen, C₁-C₁₂-alkyl; R² to R⁴ —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—,—CH₂—CH(CH₃)—, —CH₂—CH(CH₂—CH₃)—; n 1 to 5; u 2 to 2000; v 0 to 2000; w0 to 2000 together with c) at least one monomer selected from the groupof c₁) C₁-C₁₂-alkyl esters of monoethylenically unsaturatedC₃-C₈-carboxylic acids; c₂) C₁-C₁₂-hydroxyalkyl esters ofmonoethylenically unsaturated C₃-C₈-carboxylic acids; c₃) C₁-C₁₂-alkylvinyl ethers; c₄) N-vinyllactams; c₅) monoethylenically unsaturatedC₃-C₈-carboxylic acids.
 10. A polymer as claimed in claim 8, which isobtained by polymerization of a) at least one vinyl ester of aliphaticC₁-C₆-carboxylic acids in the presence of b) polyethers of the generalformula Ia, in which the variables have, independently of one another,the following meanings: R¹ and R⁸ hydrogen, C₁-C₆-alkyl; R² to R⁴—(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —CH₂—CH(CH₃)—, —CH₂—CH(CH₂—CH₃)—; n 1; u 2to 500; v 0 to 500; w 0 to 500 together with c) at least one monomerselected from the group of c₁) C₁-C₆-alkyl esters of monoethylenicallyunsaturated C₃-C₈-carboxylic acids; c₄) N-vinylpyrrolidone,N-vinylimidazole, N-vinylcaprolactam; c₅) (meth)acrylic acid.
 11. Apolymer as claimed in claim 7 with a degree of hydrolysis of from 20 to100% based on the polyvinyl ester groups.
 12. A polymer as claimed inclaim 7 with a K value of from 10 to
 200. 13. A water-soluble orwater-dispersible graft polymer which is obtained by polymerization ofa) at least one vinyl ester of aliphatic C₁-C₂₄-carboxylic acids in thepresence of b) polyglycerol of the general formula Ib,R¹OCH₂—CHOR¹⁰—CH₂—O)_(u)—R⁸)_(n)  Ib  in which the variables have,independently of one another, the following meanings: R¹ hydrogen,C₁-C₂₄-alkyl, R⁹—C(═O)—, polyalcohol residue; R⁸ and R¹⁰ hydrogen,C₁-C₂₄-alkyl, R⁹—C(═O)—; R⁹ C₁-C₂₄-alkyl; n 1 to 8; u 1 to 2000, whereinthe molecular weight of the polyethers is in the range from 300 to100,000.
 14. A polymer as claimed in claim 13, which is obtained bypolymerization of a) at least one vinyl ester of aliphaticC₁-C₁₂-carboxylic acids in the presence of b) polyglycerol of thegeneral formula Ib, in which the variables have, independently of oneanother, the following meanings: R¹ hydrogen, C₁-C₁₂-alkyl, polyalcoholresidue; R⁸ and R¹⁰ hydrogen, C₁-C₁₂-alkyl; n 1 to 5; u 1 to
 500. 15. Apolymer as claimed in claim 13, which is obtained by polymerization ofa) at least one vinyl ester of aliphatic C₁-C₆-carboxylic acids in thepresence of b) polyglycerol of the general formula Ib, in which thevariables have, independently of one another, the following meanings:R¹, R⁸ and R¹⁰ hydrogen, C₁-C₆-alkyl; n 1; u 1 to
 100. 16. A polymer asclaimed in claim 13, wherein, in addition to the vinyl esters, at leastone other monomer c) selected from the group of c₁) C₁-C₂₄-alkyl estersof monoethylenically unsaturated C₃-C₈-carboxylic acids; c₂)C₁-C₂₄-hydroxyalkyl esters of monoethylenically unsaturatedC₃-C₈-carboxylic acids; c₃) C₁-C₂₄-alkyl vinyl ethers; c₄)N-vinyllactams; c₅) monoethylenically unsaturated C₃-C₈-carboxylic acidsis used for the polymerization.
 17. A polymer as claimed in claim 13,wherein, in addition to the vinyl esters, at least one other monomer c)selected from the group of c₁) C₁-C₆-alkyl esters of monoethylenicallyunsaturated C₃-C₈-carboxylic acids; c₄) N-vinylpyrrolidone,N-vinylimidazole, N-vinylcaprolactam; c₅) (meth)acrylic acid is used forthe polymerization.
 18. A polymer as claimed in claim 13 with a degreeof hydrolysis of from 20 to 100% based on the polyvinyl ester groups.19. A polymer as claimed in claim 13 with a K value of from 10 to 200.